DESCRIPTION: This core project is aimed at the development of application neutral algorithms and software tools for biomedical systems that can potentially impact the rest of the NBCR Research Cores. This goal will be accomplished through the following three objectives: (1) Develop multiscale meshing algorithms and software for biomedical systems;(2) Develop multiscale and multiphysics simulation algorithms and software for biomedical systems, with the emphasis being on the mesoscale that covers the scale between macromolecular and cellular levels of length scale, and (3) Develop prototype multiscale/multiphysics models of two specific biomedical systems under normal and pathological conditions, using the tools from aims 1 and 2. The main applications of this core project during the proposed award period will be to develop new spatially coupled 3-D structural and functional models in cardiac cells that include: (1) realistic sub-cellular anatomical structures, such as Ca2+ -signaling micro-domains, single T-tubule of T-tubule system;and (2) spatial and temporal scales spanning from single channel ion fluxes to cross-bridge interactions and tension development. In this project, as a part of Specific Aim 1, a previously developed reconstruction code (TxBR) will be extended to incorporate recent mathematical developments in X-ray tomography and general image processing. Specifically, contrast enhancement and noise filtering algorithms will be developed and applied on the acquired data to improve image quality;and new image processing and feature extraction algorithms will be developed. The current version of the mesh generation toolchain (GAMer) will be enhanced with the development of more efficient and reliable mesh smoothing algorithms, in particular in the volumetric mesh generation. The GAMer will also be parallelized to speed up the mesh generation process and to prepare meshes for processing conducted in Aim 2 for development of Multiscale and multiphysics simulation algorithms. The primary work to be conducted at the UCSD NBCR will be the further development and extension of a flexible, powerful, and user friendly modeling toolkit (named the Finite Element Toolkit: FETK). The algorithms and tools developed in Aims 1 and 2 will be applied to studying calcium dynamics in ventricular myocytes of adult and mouse hearts. Specifically, these algorithms and tools will be used to build realistic geometries of the dyads using 3-D maps reconstructed by electron tomography to investigate local Ca2+ dynamics in a dyadic region formed by T-tubules and junctional sarcoplasmic reticulum.